Prostanoids, including prostaglandin, thromboxane, and leukotriene, belong to a family of oxidation metabolites from arachidonic acid, and play an important role in maintaining local homeostasis in the living body. Prostaglandin D2 (PGD2), a member of the prostanoid family, is known to be synthesized in various organs including, in mammals, the brain, heart, spleen, lungs, kidneys, bone marrow, stomach, intestine, skin, uterus, and eyeballs, and is known to exhibit various physiological activities (Ujihara, M. et al., Arch. Biochem. Biophys., 260: 521-531, 1988; Ito, S. et al., Prostaglandins, Leukotrienes and Essential Fatty Acids, 37: 219-234, 1989; and references cited therein). In the central nervous system, PGD2 is considered to participate in, for example, sleep introduction, regulation of body temperature, olfaction, hormone release, inflammation, and analgesia (Negishi, M. et al., Prog. Lipid Res., 32: 417-434, 1993, and the literature cited therein). Furthermore, PGD2 is known to suppress agglutination of platelets, as well as to cause relaxation of smooth muscle in organs such as the blood vessels, stomach, intestine, and uterus (Giles, H. et al., Prostaglandins, 35: 277-300, 1988, and the literature cited therein). PGD2 is a typical prostanoid released from a mast cell which plays an important role in immunological reactions. Moreover, PGD2 is known to participate in formation of pathological conditions caused by allergy, such as allergic rhinitis and bronchial asthma, through actions such as contraction of bronchial smooth muscle, migration of eosinophiles to an inflammation site, and promotion of release of inflammatory mediators from mast cells, eosinophiles, and basophiles (Negishi, M. et al., Prog. Lipid Res., 32: 417-432, 1993, and the literature cited therein). In addition, when administered locally, PGD2 has been demonstrated to have an effect to reduce intraocular pressure (Woodward, D. F. et al., Eur. J. Pharmacol., 230: 327-333, 1993).
On the basis of these findings, a substance exhibiting an action on a PGD2 receptor; for example, a PGD2-receptor-selective modulator (including an agonist and an antagonist), is considered to be a promising therapeutic drug for various diseases in which PGD2 participates. For example, physiological actions of PGD2 suggest that such a substance could be used as a wide range of drugs such as sedatives/sleeping drugs, analgesics, drugs for regulating blood pressure, platelet agglutination inhibitors, drugs for circulatory organs, drugs for suppressing motions of the stomach and intestine, anti-gastric ulcer drugs, therapeutic drugs for allergy, anti-inflammatory drugs, and prophylactic or therapeutic drugs for glaucoma.
Presently, PGD2 has been elucidated to exert its effects via a specific receptor (Coleman, R. et al., Pharmacol. Rev., 46: 205-229, 1994). However, it is known that the reaction between PGD2 and its receptor has species specificity, and thus, limitation is imposed on drug screening or evaluation or efficacy of a drug using animal tissue or an animal model (Narumiya, S. et al., Br. J. Pharmacol., 85: 367-375, 1985).
Also, a number of pharmacological analyses suggest that, with respect to human and animals, at least two subtypes of PGD2 receptor mediate various pharmacological actions of PGD2 (Woodward, D. F. et al., Eur. J. Pharmacol., 230: 327-333, 1993; Fernandes, B. et al., Eur. J. Pharmacol., 283: 73-81, 1995). For example, in human uterus smooth muscle, existence of two subtypes of PGD2 receptors; one mediating contraction caused by PGD2 and the other, conversely, mediating relaxation, has been suggested (Fernandes, B. et al., Eur. J. Pharmacol., 283: 73-81, 1995). Therefore, development of a drug which exclusively modulates, among the various actions of PGD2, a specific action of PGD2 related to prevention or improvement of pathological conditions requires understanding of the distribution of PGD2 receptor subtypes in human organs and isolation of the cDNA which codes the receptor subtypes.
Recently, after enormous research efforts, a gene which is considered to be a PGD2 subtype (hereinafter may be referred to as a DP receptor) has been cloned (Boie, Y. et al., J. Biol. Chem., 270: 18910-18916, 1995; Japanese Kokyo (PCT) Publication No. 10-507930).
Currently, studies are being conducted in order to identify, among a variety of physiological activities exhibited by PGD2, the specific physiological activity or activities in which the DP receptor participates. As a result of such studies, one report describes that analysis on the DP receptor, through expression in the rat brain, has revealed that distribution of the DP receptor does not coincide with the sleep induction sensitive region of PGD2 (Gerashchenko, D. et al., J. Neurochem., 71: 937-945, 1998). That is, this report suggests the presence of a PGD2 receptor which is different from the DP receptor, and thus, verification of the presence of such a new receptor and identification of the functions thereof are of keen interest.
The subject matter to be handled by the present invention is to find a second human PGD2 receptor subtype other than the DP receptor, and to provide a method of identifying a substance which acts on the second human PGD2 receptor subtype and which is useful in the treatment and prevention of a variety of diseases; for example, a substance which acts as a selective modulator (including an agonist and an antagonist).